The present invention is directed to treating gastrointestinal disorders, including inflammatory bowel disease, particularly colitis, and to methods of increasing the short chain fatty acid content of the colon.
It is now well recognized that short chain fatty acids (SCFA), particularly those having from 1 to 4 carbon atoms are implicated in the treatment of numerous diseases and/or conditions of the gastrointestinal tract, particularly the colon. It is universally accepted that SCFA are a major energy source for the colon and other related tissues.
SCFA are liberated on the bodies of mammals predominately through the anaerobic fermentation of undigested carbohydrates in the colon. Of the SCFA, acetic acid, propionic acid, and butyric acid account for 90-95% of SCFA in the colon. Kim, Young-In, xe2x80x9cShort-Chain Fatty Acids in Ulcerative Colitisxe2x80x9d, NUTRITION REVIEWS, Vol. 56, 1, pp. 17-24. The ratio of acetic (xe2x80x9cacetatexe2x80x9d) to propionic (xe2x80x9cpropionatexe2x80x9d) to butyric (xe2x80x9cbutyratexe2x80x9d) acids is about 1:0.31:0.15, and the proportions vary with the substrate (largely roughage), composition of anaerobic flora, and pH. However, the fermentation products are remarkably similar in the human colon, the large cecum of herbivores, and bovine rumen. Soergel, K. H., xe2x80x9cColonic Fermentation: Metabolic and Clinical Implicationsxe2x80x9d, CLIN INVESTIG 72, 742-48 (1994). Deficiencies in SCFA have been associated with inflamed colonic mucosa, Sheppach, W., et al., xe2x80x9cEffects of Short-Chain Fatty Acids on the Inflamed Colonic Mucosaxe2x80x9d, SCAND. J. GASTROENTEROL, Suppl. 222, pp. 53-57 (1997) and ulcerative colitis, W. Sheppach, xe2x80x9cShort-Chain Fatty Acids Improve Epithelia in Ulcerative Colitis? Speculation or Mechanismxe2x80x9d, Falk Symp. (1994), 73 (Short Chain Fatty Acids), pp. 206-213; diversion colitis, Soergel, op. cit.; and other disorders.
Studies have shown that increasing SCFA levels brings about therapeutically significant improvements in areas such as prevention of Colorectal Cancer, W. Sheppach, et al. xe2x80x9cRole of Short-Chain Fatty Acids in the Prevention of Colorectal Cancerxe2x80x9d, EUR J. CANCER, Vol. 31A, No. 7/8, pp. 1077-80, 1995; treatment of colitis, W. Sheppach, xe2x80x9cEffects of Short Chain Fatty Acids on Gut Morphology and Functionxe2x80x9d, GUT 1994, Supplement 1, pp. 35-38; ulcerative colitis, Jorgersen, J. R., et al., xe2x80x9cInfluence of Feces from Patients with Ulcerative Colitis on Butyrate Oxidation in Rat Colonocytesxe2x80x9d, DIGESTIVE DISEASES AND SCIENCES, Vol. 44, 10 pp. 2099-2109 (1999), Kim, op. cit., Sheppach, Falk Symp. (1994), 73 (Short Chain Fatty Acids), op. cit. (pp. 206-213); and diversion colitis Soergel, op. cit. In addition, SCFA""s are implicated in immune system response, Perez, R., et al. xe2x80x9cSelective Targeting of Kupffer Cells with Liposomal Butyrate Augments Portal Venous Transfusion-Induced Immunosuppressionxe2x80x9d, TRANSPLANTATION, Vol. 65, 10, p. 1294-98, 1998; Perez, R., et al. xe2x80x9cSodium Butyrate Upregulates Kupffer Cell PGE2 Production and Modulates Immune Functionxe2x80x9d, J. SURGICAL RES., 78 pp. 1-6 (1998); apoptosis in hepatic tumors, Watkins, S. M., et al.; xe2x80x9cButyric Acid and Tributyrin Induce Apoptosis in Human Hepatic Tumor Cellsxe2x80x9d, J. Dairy Res., 66, pp. 559-67 (1999); and in inhibiting fluid loss in chloera-infected mammals, Rabboni, G. H., et al., xe2x80x9cShort-Chain Fatty Acids Inhibit Fluid and Electrolyte Loss Inducted by Cholera Toxin in Proximal Colon of Rabbit In Vitroxe2x80x9d, DIGESTIVE DISEASES AND SCI., Vol. 44, 8, pp. 1547-53 (1999).
In most studies reported above, SCFA were administered in the form of their soluble salts, i.e., alkali metal acetates, propionates, and butyrates. The xe2x80x9catexe2x80x9d salt suffix has been used rather uniformly in the medical literature to refer to both the salt and free acid forms of the SCFA, unless indicated to the contrary.
Administration of SCFA, notably butyrate, both in oral form and as an enema or suppository, has been found to affect a variety of disorders, as indicated above. However, butyric acid and its salts are notoriously odorous, so much so that patients often discontinue treatment because of the foul odors involved. In U.S. Pat. No. 5,569,680, administration of glycerine tris(butyrate ester), known as tributyrin, is said to improve patient compliance through use of a less odiferous substance. However, tributyrin is still somewhat odiferous, perhaps due to incomplete esterification, or due to partial hydrolysis liberating butyric acid. Thus, the administrative problems of butyrate, while ameliorated by tributyrin, are not completely solved by its use. Moreover, as indicated by Smith, J. G., et al. xe2x80x9cButyric Acid from the Diet: Actions at the Level of Gene Expressionxe2x80x9d, CRIT. REV. IN FOOD SCI., Vol. 38, 4, pp. 259-97 (1998), the effects of butyrate derivatives such as arginine butyrate, butyramide, monobutyrin, and tributyrin are not the same, and thus additional butyrate-releasing compounds are desired.
The present invention pertains to a method of increasing the short chain fatty acid (SCFA) content of the gastrointestinal tract, in particular the colon. The present invention also pertains to a method for treating various gastrointestinal disorders by supplying a substantially odor-free compound which can be absorbed and/or metabolized in situ in the gastrointestinal tract to liberate SCFA, and to compounds suitable for use therein.